This invention relates to a controlled-release pharmaceutical preparation which includes an analgesic which is in admixture with an injectable oil, and optionally containing a pharmaceutically acceptable excipient. The preferred analgesic is nalbuphine free base or a pharmaceutically acceptable salt of nalbuphine (preferably nalbuphine-HCl). The preferred injectable oil includes sesame oil, ethyl ester of peanut oil, soybean oil, and any combinations thereof. The pharmaceutical composition is further characterized by its containing of microparticles with size less than 100 xcexcm. The controlled-release pharmaceutical preparation exerts a long-acting analgesic effect when being administered intramuscularly, subcutaneously, intracerebroventricularly or percutaneously. A process for preparing the controlled-release pharmaceutical preparation is also disclosed herein.
An ideal analgesic should exhibit short onset time, should be potent and long-acting, should cause no addiction, no inhibition of the cardiac or cardiovascular system and no respiratory inhibition, and should have rare other adverse effects.
Local anesthetics like xylocaine or bupivacaine are effective to relieve pain only within limited areas. In addition, local anesthetics are short-acting and exhibit duration of action normally no more than 6 hours even when being given intracerebroventricularly. Therefore, local anesthetics are not satisfactory for the relief of acute and severe pain caused by cardiac, pulmonary, abdominal, osteopathic or obstetrical surgery, severe burn injury and terminal stage of cancer.
Non-narcotic analgesics, such as aspirin and acetaminophen, relieve pain of only low intensity, such as pain due to headache or toothache, but they do not help in the case of severe pain. For the pain of high intensity and widespread in origin, narcotic analgesics have been particularly referred to in literature, amongst which morphine, meperidine and fentanyl are reported to interact with specific receptors (i.e. mu receptor) in the CNS and exhibit potent analgesic activity. However, all the narcotic analgesics exhibit common disadvantages such as addiction and respiratory inhibition (Hayes, A. G. et al., Br. J. Pharmacol., Vol.79, pp.731, 1983). The most unwanted problem associated with the long-term use of narcotic analgesics is the incidence of addiction. In addition, it is not unusual that narcotic analgesics induce severe respiratory depression and even death in patients with poor respiratory function or post cardiac or chest surgery. Moreover, narcotic analgesics exhibit a relatively short duration of action and, therefore, under normal conditions, a dosing interval of 3-5 hours is required so as to maintain of the intended analgesic effect thereof. Even when the agent is directly administered to the spinal marrow, the duration of action would not last for a period of more than 48 hours. In addition, if a larger dose of the agent, e.g. morphine of 0.5-1.0 mg/dose, is used to provide a prolonged analgesic effect, fatal respiratory depression is likely to occur (Baxter. A. D. et al., Can. J. Anesth., Vol. 36. pp.503, 1989).
Recently, there have been developed a new class of opioids called narcotic agonist-antagonist analgesics, the representatives of which include nalbuphine, buprenorphinc and butorphanolm, the chemical structures of which are shown in FIG. 1. These analgesics are reported to exhibit a dual action of agonism and antagonism on opioids-receptors (Schmidt, W. F. et al., Drug Alcohol Depend., Vol. 14, pp.339, 1985). For instance, nalbuphine is an antagonist for the mu receptor and an agonist for the kappa receptor. After a continuous administration period of six months, nalbuphine appears to cause no significant addiction while resulting in only slight respiratory inhibition. Due to these observed pharmacological properties, the adverse effects normally associated with narcotic analgesics have been greatly improved by this new class of narcotic analgesics, which decrease the incidence of addiction and diminish the inhibitory effect on the respiratory system.
The analgesic potency of this new class of narcotic analgesics have been investigated and compared with the more traditional class of narcotic analgesics which elicit addiction. It has been found that the doses needed to elicit the same analgesic effect by morphine, buprenorphine, nalbuphine and butorphanol are 10 mg, 0.3 mg, 10 mg and 2 mg, respectively (Shafer, S. L. et al., Anesthesiology, Vol. 74, pp.53, 1991). According to the report of Schmidt, W. K. et al. (1985), supra, nalbuphine is most widely used amongst this new class of narcotic analgesics and it exhibits excellent therapeutic efficacy. In clinical use, nalbuphine exhibits only slight respiratory inhibition and is therefore safer than the traditional narcotic analgesics which elicit addiction.
Nalbuphine has been found to be effective in control of severe and deep pain caused by cardiac, pulmonary, abdominal, osteopathic or obstetrical surgery, severe burn injury and the terminal stage of cancer via various administration routes, such as intramuscular, intravenous and intrathecal administrations (Schmidt, W. K. et al. (1985), supra). Wang, J. J. et al. (Ma. Tsui. Hsueh. Tsa. Chi., Vol. 23, pp.3, 1985) have reported that the effect of nalbuphine can only last for 3-5 hours after intravenous administration and 6-8 hours by intrathecal injection, respectively. However, severe pain usually cannot be relieved in such short periods of time. Therefore, the clinical use of nalbuphine is still not satisfactory due to its short duration of action.
An improvement that effectively extends the duration of action of a target drug is a significant advance in the field of medicine, as such improvement is considered to enable the more economical utilization of medical resources. To achieve this purpose, a widely employed approach is to modify the dosage form of a drug that is normally eliminated rapidly in vivo, so that the duration of action of the drug is extended.
In order to control or prolong the duration of action of a target drug during clinical use, various pharmaceutical preparations have been developed. For example, the target drug may be coated with cyclodextrin or acrylic polymers, or manufactured in the form of microcapsules or microparticles, so that release of the drug is controlled or delayed. However, pharmaceutical preparations in such forms do not always provide effective controlled release of active component(s) therefrom.
It has been found that for narcotic analgesics that may cause addiction, it is possible to decrease the release rate and the side effects thereof via subcutaneous administration. The subcutaneous area has less blood flow and more adipose tissue than other parts of the human or animal body, so that when a lipophilic drug is subcutaneously administered into the subcutaneous areas, the release thereof slows down.
With respect to the intracerebroventricular or spinal cord administration, the increased duration of action and the decreased side effects of narcotic analgesics, such as morphine, fentanyl, buprenorphine and nalbuphine, have been investigated by Rutter, D. V. et al. (Br. J. Anesth., Vol. 53, pp. 915, 1981). In addition to the administration routes described above, the percutaneous administration of narcotic analgesics is also considered to be promising. Hill, H. F. et al. (Eur., J. Pharmacol., Vol. 119, pp.23, 1985) have proposed a dosage form of fentanyl for percutaneous administration having a safety range of 0.6-3 xcexcg/ml, which is the same as that of narcotic analgesics acting on the mu-receptor.
In U.S. Pat. No. 4,673,679 issued to Bruce et al. on Jun. 16, 1987, it is stated that morphine, fentanyl, buprenorphine and nalbuphine derivatives in the sublingual, buccal or nasal dosage form exhibit enhanced bioavailability. However, Bruce et al. did not investigate the analgesic action and the long-acting effect of nalbuphine free base. No injectable dosage form of nalbuphine free base suitable for therapeutic use has been described.
Accordingly, there still exists a need for a new dosage form of nalbuphine free base or nalbuphine HCl which effectively extends the duration of action of nalbuphine free base in vivo.
Therefore, it is an object of this invention to provide a controlled-release pharmaceutical preparation which is an oil suspension comprising an analgesic which is a nalbuphine free base or a pharmaceutically acceptable salt of nalbuphine, which is in admixture with an injectable oil, so that the duration of action of the analgesic in relieving pain is prolonged in vivo. The pharmaceutically acceptable salt of nalbuphine includes acid addition salt of nalbuphine or an alkali or alkaline earth metal salt thereof. The most favorable pharmaceutical acceptable salt of nalbuphine is nalbuphine HCl. The preferred injectable oil includes sesame oil, ethyl ester of peanut oil, soybean oil, and any combination of the oil. Sesame oil is the most favorable injectable oil. Optionally, a pharmaceutically acceptable excipient, such as aluminum stearate, chlorobutanol hydrate, methyl paraben, propyl paraben, and any combinations thereof, can be added to the oil suspension.
The controlled-release pharmaceutical preparation of the present invention is further characterized by its formation of microparticles in the oil suspension with size less than 100 xcexcm, most preferably less than 50 xcexcm. The microparticles of the oil suspension is formed by mixing the analgesic and the injectable oil in an ultra high energy mixing equipment, such as MicroFludizer high pressure homogenizer, Emulsiflex, and Manton-Gaulin, preferably under a pressure of 10,000 to 30,000 psi, and most favorably at about 14,000 psi. The preferred length of time to operate the ultra high energy mixing equipment is about 10 to 75 minutes.
Also preferably, the controlled-release pharmaceutical preparation of the present invention is administered via an intramuscular, subcutaneous, intracerebroventricular or percutaneous route, or for direct injection into the spinal marrow. The most preferred route is through intramuscular injection.
It is contemplated that the injectable oil suspension of this invention possesses the desired properties for an analgesic as discussed above, such as being long acting, fast acting (short onset time), and nonaddictive, and not causing other undesirable side effects such as inhibition of the cardiac or cardiovascular system, respiratory system, etc.
It is another object of this invention to provide a process for making a controlled-release pharmaceutical preparation which includes the steps of: (1) mixing the analgesic with the injectable oil to form the oil suspension, and (2) treating the oil suspension with an ultra high energy mixing equipment to form microparticles with a particle size less than 100 xcexcm, preferably no more than 50 xcexcm in size. The preferred analgesic is nalbuphine free base or a pharmaceutically acceptable salt of nalbuphine. The preferred pharmaceutically acceptable salt of nalbuphine includes acid addition salt of nalbuphine or an alkali or alkaline earth metal salt thereof. The most favorable pharmaceutical acceptable salt of nalbuphine is nalbuphine HCl. The preferred injectable oil includes sesame oil, ethyl ester of peanut oil, soybean oil, and any combinations thereof.
Preferably, the injectable oil is pre-heated to about 45xc2x0 C. before mixing with the analgesic. After mixed or homogeneously suspended with the analgesic, the analgesic-injectable oil mixture is cooled to room temperature, and then treated with an ultra high energy mixing equipment. Examples of the ultra high energy mixing equipment include, but are not limited to, MICROFLUIDIZER high pressure homogenizer (Model 110-S or 110-Y, Microfluidics Corp., Newton, Mass.), EMULSIFLEX (Avestin Inc., Ottawa, Ontario, Canada), or Manton-GAULIN (APV Gaulin Rannie, St. Paul, Minn.). The preferred ultra high energy mixing equipment is MICROFLUIDIZER high pressure homogenizer M110-Y.
Also preferably, the analgesic can be pre-mixed with a pharmaceutically acceptable excipient, such as aluminum stearate, chlorobutanol hydrate, methyl paraben, propyl paraben, and any combinations thereof.
This invention provides an injectable oil suspension containing nalbuphine free base or nalbuphine HCl, which exhibits a longer duration of action when being administered intramuscularly or subcutaneously. The injectable oil suspension according to this invention may be used in the treatment of living subjects, preferably mammals, and in particular humans suffering severe pain.